Lyophilization is a commonly used method for preparing active ingredients into more solid forms of pharmaceuticals. For example, an active ingredient such as AT III, which is an alpha2-glycoprotein normally present in plasma and is a plasma inhibitor of thrombin, has been shown to have relatively poor stability in solution. Accordingly, AT III has been processed into lyophilized preparations.
It has been proposed that lyophilization reduces or inhibits the degradation of the active ingredient by removing solvent components in a formulation to levels that no longer support chemical reactions or biological growth. Additionally, it is believed that the removal of solvent reduces molecular mobility, reducing potential for degradative reaction. Also, it is desirable for crystallizing excipients (e.g., amino acids and salts), which are commonly used in lyophilized products, to crystallize as completely as possible during freezing in order to provide a solid matrix to support cake structure. However, a number of previous attempts to lyophilize aqueous pharmaceutical formulations have failed to achieve satisfactory degrees of crystallization. For example, the various freezing and/or annealing steps of a typical lyophilization protocol itself have been shown to be inefficient in promoting crystallization. Moreover, it has been suggested that the presence of certain crystallizing excipients (e.g., alanine and sodium chloride) can inhibit or reduce the crystallization of either excipient thereby also limiting the extent of crystallization.
While several attempts have been made to lyophilize aqueous pharmaceutical formulations, there remains a need for effective lyophilization methods and compositions prepared therefrom.